Is BRCA2 p.Ile2675Val (c.8023A>G) pathogenic?

BRCA2 p.Ile2675Val (c.8023A>G) is classified Pathogenic in BRCA2 (ClinVar, Expert panel, 19 submitters; last evaluated 2024-06-11). AlphaMissense: likely benign (0.2041); Very rare (popmax 0.00223%, eas); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Ile2675Val (c.8023A>G)?

BRCA2 p.Ile2675Val (c.8023A>G) is associated with BRCA2-related cancer predisposition, gastric cancer, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Ile2675Val (c.8023A>G) in the general population?

BRCA2 p.Ile2675Val (c.8023A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Ile2675Val (c.8023A>G)?

AlphaMissense predicts likely benign (score 0.2041) — an in-silico prediction, not a clinical call.

BRCA2 p.Ile2675Val

c.8023A>G · rs397507954 · VCV52475

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 19 submitters

AlphaMissense

likely benign

0.2041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PVS1 PP4_Strong

Curation rationale (ClinGen, verbatim)

The c.8023A>G variant in BRCA2 is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 2675 (p.Ile2675Val). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and mini-gene assays demonstrated that the variant impacts splicing by creation of a donor site, resulting in skipping of 309nt of exon 18 (PMIDs: 18424508, 22505045, 28339459). All studies report no wild-type transcript from the variant allele. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1612 (based on Cosegregation LR=605.1; Pathology LR=0.88; Co-occurrence LR=1.05; Family History LR=2.88), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2041	likely benign ⚠ discordant with ClinVar
REVEL	0.88	moderately pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.99	donor gain · deltas
Pangolin	Δ0.87	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.84e-05% 1/1,461,706 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BRCA2
Protein: p.Ile2675Val
Coding: c.8023A>G
MANE Select: NM_000059
dbSNP: rs397507954
Type: single nucleotide variant
Location: chr13:32363225 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2675: the 'interaction with sem1' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: gastric cancer hereditary breast ovarian cancer syndrome medulloblastoma prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRCA2 p.Ile2675Arg Uncertain significance ★ ⚠ same residue
BRCA2 p.Ile2675Leu Uncertain significance ★ same residue
BRCA2 p.Ile2675Met Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ile2675= Likely benign ★ same residue
BRCA2 p.Ile2675fs Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/brca2-p-ile2675val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown